[Clinicopathological and molecular characteristics of primary small cell neuroendocrine carcinoma of the breast: an analysis of nine cases].

Abstract

Objective: To investigate the clinicopathological and molecular characteristics of primary small cell neuroendocrine carcinoma (SCNEC) of the breast. Methods: A retrospective analysis was conducted on the 9 patients with SCNEC of the breast diagnosed at the Department of Pathology of the First Affiliated Hospital of Soochow University, Suzhou, China from January 2011 to December 2025. Hematoxylin-eosin (HE) staining, immunohistochemistry (IHC), and next-generation sequencing (NGS) were employed to evaluate the clinicopathological characteristics, immunophenotypes, and molecular alterations. Treatment and follow-up data were also reviewed. Results: All 9 patients were female, with an age of 54.0 (45.0, 67.5) years. The maximum tumor diameter ranged from 1.8 to 10.6 cm. Pathological morphology exhibited features of small cell carcinoma. Necrosis was observed in 7 cases, intravascular tumor thrombus in 2 cases, and tumor involvement of the nipple epidermis in 1 case. All cases were positive for CKpan, chromongranin A and synaptophysin, while partial expression was noted for CD56 (7/9), ER (3/9), PR (1/9), TRPS1 (5/9), and GATA3 (3/9). All cases showed mutant-type p53 expression and loss of RB1 protein expression. The Ki-67 proliferation index ranged from 60% to 90%. NGS showed that TP53 was the most frequently mutated gene, with missense mutations identified in 3 of the 4 cases tested. Tumor mutational burden (TMB) analysis showed that all 4 cases had TMB <10 Muts/Mb, falling into the low TMB category. Microsatellite instability analysis revealed that 1 case was microsatellite instability-high, with a concurrent MSH6 frameshift mutation, indicating mismatch repair deficiency. Among the 7 patients who underwent surgery, 1 received neoadjuvant chemotherapy with marked tumor regression, and 4 received postoperative adjuvant therapy. The other 2 patients with advanced disease did not undergo surgery but received systemic chemotherapy after core needle biopsy. Follow-up data were available for 6 of the 9 patients, with follow-up periods ranging from 3 to 87 months. Three patients were alive, and three patients died at 22, 24, and 27 months after surgery, respectively. Conclusions: Primary SCNEC of the breast is a rare type of highly aggressive malignancy. Its diagnosis requires the exclusion of metastasis from other primary sites. The immunophenotype is mostly ER/PR-negative in this cohort, and GATA3 and TRPS1 are of limited value in confirming a mammary origin. p53 mutation and loss of RB1 expression are common molecular alterations in this tumor.